A Six-week Study Comparing the Efficacy and Safety of Tiotropium Plus Formoterol to Salmeterol Plus Fluticasone in Chronic Obstructive Pulmonary Disease (COPD)

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT00239421

Collaborator

(none)

605

Enrollment

Locations

Duration (Months)

10.8

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To compare the efficacy and safety of tiotropium plus formoterol in comparison to salmeterol plus fluticasone in COPD patients.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Test: Tiotropium 18 µg per day (one inhalation capsule) plus 12 µg formoterol twice daily (two times one inhalation capsule) Drug: Reference: Salmeterol MDI 50 µg (2 puffs of 25 µg each) b.i.d., plus fluticasone propionate MDI 500 µg (2 puffs of 250 µg each) b.i.d.	Phase 4

Detailed Description

Tiotropium (Spiriva®) is a once-daily inhaled anticholinergic for the treatment of COPD. A six-week, multicentre, randomized, double-blind, parallel group study was conducted to compare the efficacy and safety of the free combination of tiotropium 18 µg once daily plus formoterol 12 µg b.i.d. [Tio+For] to salmeterol 50 µg b.i.d. plus fluticasone 500 µg b.i.d. [Sal+Flu] in COPD patients. Information regarding the differential efficacy and safety of the two different combinations may be essential for physicians to make informed choices of therapy for COPD patients considered candidates for combination therapy.

Following an initial screening visit, subjects entered a two or four-week run-in period in which they received ipratropium (Atrovent®) on a regular basis. At the second visit (Baseline), subjects were randomized into the six-week, double blind portion of the study in which they received either Tio+For or Sal+Flu. After three weeks of treatment, an interim visit was scheduled. After six weeks of treatment, a 12-hour profile of pulmonary function testings (FEV1, FVC) was obtained. Spirometric measurements were performed at pre-dose and 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dosing. There were two co-primary endpoints: FEV1 area under the curve for the time period 0 to 12 hours (FEV1 AUC0-12) and peak FEV1.

The efficacy evaluation (intention-to-treat) comprised 592 patients [Tio+For: N=297, Sal+Flu:

N=295]. The two treatment groups were comparable with regard to demographic data and baseline disease characteristics [Baseline FEV1 (±SE): Tio+For: 1.310 L (±0.026 L); Sal+Flu: 1.325 L (±0.025 L)]. Adjustment was done for baseline and centre-effects.

Study Hypothesis:

The following primary hypotheses (one-sided) were tested with regard to superiority (all means are adjusted means):

H01: FEV1AUC(0-12 hours) (tiotropium+formoterol) <= FEV1AUC (0-12 hours) (salmeterol+fluticasone) versus H11: FEV1AUC(0-12 hours) (tiotropium+formoterol) > FEV1AUC 0-12 hours(salmeterol+fluticasone)

It was stipulated in the protocol that, if the null hypothesis H01 was rejected in favour of

H11, then the following hypothesis would be tested:

H01: Peak FEV1 (tiotropium+formoterol) <= Peak FEV1 (salmeterol+fluticasone) versus H11: Peak FEV1 (tiotropium+formoterol) > Peak FEV1 (salmeterol+fluticasone)

Each step was only considered confirmatory providing all previous steps were successful. If any of the previous steps were not successful, any analysis of the current step would have been considered descriptive.

Comparison(s):

Test therapy:

Test product: Tiotropium inhalation capsules plus formoterol inhalation capsules Dose: 18 µg tiotropium per day (one capsule), 12 µg formoterol twice daily (two times one capsule) Mode of administration: inhalation via the Handihaler device (tiotropium), inhalation via the Blue Inhaler device (formoterol)

Reference therapy:

Test product: Salmeterol plus fluticasone propionate Dose: Salmeterol 50 µg (2 puffs of 25 µg each) b.i.d., fluticasone propionate 500 µg (2 puffs of 250 µg each) b.i.d.

Mode of administration: inhalation via MDI

The treatment duration was 42 days each. Primary endpoint measurements were performed on the last treatment day.

Study Design

Study Type:

Interventional

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double

Primary Purpose:

Treatment

Official Title:

A Six-Week, Randomized, Double-Blind, Quadruple-Dummy Parallel Group Multiple Dose Study Comparing the Efficacy and Safety of Tiotropium Inhalation Capsules Plus Formoterol Inhalation Capsules to Salmeterol Inhalation Aerosol Plus Fluticasone Inhalation Aerosol in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Start Date :

Nov 1, 2003

Actual Primary Completion Date :

Sep 1, 2004

Study Completion Date :

Sep 1, 2004

Outcome Measures

Primary Outcome Measures

The primary efficacy variable was forced expiratory volume in one second (FEV1). There were two co-primary endpoints: FEV1 area under the curve for the time period 0 to 12 hours [FEV1 AUC (0-12)] and peak FEV1 measured after 6 weeks of treatment. []

Secondary Outcome Measures

Secondary endpoints were trough FEV1, trough FVC, peak FVC and FVC AUC (0-12) measured at the same times as FEV1 after six weeks of treatment, individual FEV1 and FVC profiles, rescue medication use, peak expiratory flow, results of safety measurements. []

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All patients must sign an informed consent prior to participation in the trial, which includes medication washout and restrictions.
All patients must have a diagnosis of chronic obstructive pulmonary disease according to the GOLD criteria and must meet the following spirometric criteria:

a post-bronchodilator FEV1 < 80% of predicted normal, a post-bronchodilator FEV1/FVC < 70% at Visit 1, and a morning FEV1 <= 65% predicted at Visit 2.

Male or female patients 40 years of age or older.
Patients must be current or ex-smokers with a smoking history of more than 10 pack-years.
Patients must be able to perform technically acceptable pulmonary function tests.
Patients must be able to inhale medication in a competent manner from the HandiHaler® device, the Blue Inhaler device, and from a metered dose inhaler (MDI).

Exclusion Criteria:

Patients with significant diseases other than COPD.
Patients with a recent history (i.e., six months or less) of myocardial infarction.
Patients who have been hospitalized for heart failure (NYHA class III or IV) within the past year.
Any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
Patients with a history of cancer within the last five years.
Patients with known narrow-angle glaucoma.
Patients with a history of asthma, allergic rhinitis or atopy or who have a total blood eosinophil count >= 600/mm3.
Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
Patients with known active tuberculosis.
Patients with significant alcohol or drug abuse within the past two years.
Patients who have undergone thoracotomy with pulmonary resection.
Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the Screening Visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program that will not be maintained throughout the study.
Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy.
Patients who are being treated with antihistamines (H1 receptor antagonists) for asthma or excluded allergic conditions.
Patients who have taken an investigational drug within one month or six half lives prior to Visit 1.
Patients who have been treated with oral beta-adrenergics within one month prior to Visit 1.
Patients who have been treated with antileukotrienes or leukotriene receptor antagonists for any disease within one month prior to Visit 1.
Patients who have been treated with oral steroids within six weeks prior to Visit 1.
Patients who have been treated with monoamine oxidase inhibitors or tricyclic antidepressants within one month prior to Visit 1.
Patients who have been treated with cromolyn sodium or nedocromil sodium within one month prior to Visit 1.
Patients who have been treated with inhaled steroids within two months prior to Visit 1, including combinations of inhaled steroids and long-acting beta-adrenergics.
Patients with known hypersensitivity to anticholinergic drugs, beta adrenergics, lactose or any other components of the inhalation capsule delivery system or any other components of the aerosol delivery systems.
Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception for the previous three months.
Patients with any respiratory infections in the six weeks prior to the Screening Visit (Visit 1) or during the run-in period.
Patients who are currently participating in another study.
Patients requiring more than eight puffs of salbutamol on three or more consecutive days during the run-in period.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Med. Uni.-Klinik Graz	Graz	Austria	8036
2	Klinikum Kreuzschwestern Wels	Wels	Austria	4600
3	Boehringer Ingelheim Investigational Site	Wien	Austria	1120
4	Sint-Vincentius Ziekenhuis	Antwerpen	Belgium	2018
5	CHU Notre Dame des Bruyères	Chênée	Belgium	4032
6	Heilig Hartziekenhuis Campus Menen	Menen	Belgium	8930
7	Boehringer Ingelheim Investigational Site	Vosselaar	Belgium	2350
8	Lungemedicinsk Forskning 2B	Aarhus	Denmark	DK-8000
9	Bispebjerg Hospital	Copenhagen NV	Denmark	DK-2400
10	Amtssygehuset i Gentofte	Hellerup	Denmark	DK-2900
11	Hvidovre Hospital	Hvidovre	Denmark	DK-2650
12	Odense Universitetshospital	Odense C	Denmark	DK-5000
13	Centre Hospitalier Germon et Gauthier	Beuvry	France	62660
14	Hôpital Gabriel Montpied	Clermont Ferrand cedex 1	France	63003
15	Boehringer Ingelheim Investigational Site	Grenoble	France	38100
16	Boehringer Ingelheim Investigational Site	Lagord	France	17140
17	Clinique de la Louvière	Lille Cedex	France	59042
18	Boehringer Ingelheim Investigational Site	Berlin	Germany	13597
19	MEDARS GmbH	Berlin	Germany	14057
20	Klinikum der Ruhr-Universität Bochum	Bochum	Germany	44791
21	ClinGuard GmbH	Dortmund	Germany	44263
22	Boehringer Ingelheim Investigational Site	Frankfurt/Main	Germany	60323
23	Inamed Research GmbH & Co. KG	Gauting	Germany	82131
24	Boehringer Ingelheim Investigational Site	Gelnhausen	Germany	63571
25	am Krankenhaus Großhansdorf	Großhansdorf	Germany	22927
26	Pneumologisches Forschungsinstitut GmbH	Hamburg	Germany	20535
27	Boehringer Ingelheim Investigational Site	Hannover	Germany	30176
28	Boehringer Ingelheim Investigational Site	Kiel	Germany	24105
29	Klinikum der Universität zu Köln	Köln	Germany	50931
30	ClinPharm International GmbH & Co. KG	Leipzig	Germany	04229
31	Otto-von-Guericke-Universtität Magdeburg	Magdeburg	Germany	39120
32	Boehringer Ingelheim Investigational Site	Minden	Germany	32423
33	Boehringer Ingelheim Investigational Site	München	Germany	80634
34	Poli Longziekten	Almelo	Netherlands	7609 PP
35	lokatie Langendijk	Breda	Netherlands	4819 EV
36	Catharina Hospital	Eindhoven	Netherlands	5623 EJ
37	Polikliniek Longziekten	Heerlen	Netherlands	6419 PC
38	Poli Longziekten	Hengelo	Netherlands	7555 DL
39	UMC St Radboud ziekenhuis	Nijmegen	Netherlands	6525 GA
40	Sint Franciscus Gasthuis	Rotterdam	Netherlands	3045 PM
41	Afdeling CardioSearch	Veldhoven	Netherlands	5504 DB
42	Tiervlei Trial Centre	Bellville	South Africa	7530
43	Boehringer Ingelheim Investigational Site	Bloemfontein	South Africa	9301
44	UCT Lung Institute	Cape Town	South Africa	7700
45	Boehringer Ingelheim Investigational Site	Cape Town	South Africa	8001
46	Boehringer Ingelheim Investigational Site	Durban	South Africa	4001
47	St. Augustine Hospital	Durban	South Africa	4001
48	QdotPharma	George	South Africa	6529
49	Boehringer Ingelheim Investigational Site	Johannesburg	South Africa	2193
50	Boehringer Ingelheim Investigational Site	Paarl	South Africa	7646
51	Boehringer Ingelheim Investigational Site	Pretoria	South Africa	0083
52	Lung- och allergikliniken, Länssjukhuset Ryhov	Jönköping	Sweden	S-551 85
53	Endokrinologmott/Medicinkliniken	Motala	Sweden	591 85
54	Lung och allergikliniken	Stockholm	Sweden	141 86
55	Lung och allergikliniken	Stockholm	Sweden	171 76
56	Lung- och allergikliniken, Universitetssjukhuset	Umeå	Sweden	S-901 85